Project Abstract As genomic sequence data are being produced faster and at lower cost, the most significant challenge in clinical genetic testing today is variant classification. Currently, there are marked differences in variant classification among clinical laboratories, with clinically significant discrepancies in 29% of variants interpreted. Variants that were previously categorized as pathogenic are now known to be benign with the increasing availability of more ethnically diverse reference data, and this is issue is more common for individuals of non-European ancestry. At the same time, a substantial percentage of variants are classified as of unknown significance (VUS), with inadequate data to prove or disprove a pathogenic association with a medical condition. Progress in interpreting genomic data, however, will lead to greater agreement on how to call variants that are currently subject to discrepant classifications and the question arises about how will that information about reclassification of variants reach patients and their health care providers. There is currently no definitive guidance from professional organizations or opinion leaders about how to handle variant reclassification, and the field seems uncertain how to respond. Stakeholders including laboratories, providers, patients, and payers likely have different perspectives and opinions. To provide an empirical foundation for this critical discussion and develop guidance for the field, we will conduct a series of activities including focus groups and online surveys with 3 key stakeholder groups: patients, providers, and the laboratories. We will have three working groups to define the legal, ethical, and economic aspects to consider and develop possible solutions. We will host an annual meeting with experts on genetics, clinical laboratory operations, reimbursement, health economists, regulatory and legal issues, and ethics, along with clinicians and patient advocates, to provide guidance for the project, to review the data and develop a set of options and a final set of recommendations to address this issue. We will seek input on possible solutions from stakeholders through an online survey and arrive at final recommendations that we will present to the genomics community and to board of the American College of Medical Genetics and Genomics to guide the adoption of an acceptable and responsible policy in for this rapidly changing area.